This invention relates to the preparation of carbocyclic analogues of thymine nucleosides, to the use of such compounds in the treatment of viral infections, and to certain novel compounds.
Thymidine is 5-methyl-2'-deoxyuridine. Therefore, carbocyclic analogues of thymine nucleosides are also carbocyclic analogues of 5-substituted-2'-deoxyuridines.
The term "carbocyclic analogue of a nucleoside" designates a compound that has the same chemical structure as the nucleoside except that the oxygen atom of the furanose moiety of the nucleoside is replaced by a methylene group in the carbocyclic analogue; or, differently expressed, in the carbocyclic analogue a cyclopentane ring replaces the tetrahydrofuran ring of the analogous nucleoside. Such nucleoside analogues were designated carbocyclic analogues of nucleosides by Shealy and Clayton, Journal of the American Chemical Society, Volume 88, pages 3885-3887, 1966. The natural nucleosides and many of their true nucleoside analogues are subject to the action of enzymes (phosphorylases and hydrolases) that cleave the nucleosides to the pentose and purine or pyrimidine moieties. For example, it has been reported by C. Desgranges et al. (Biochemical Pharmacology, Vol. 32, pages 3583-3590, 1983) that various 5-substituted-2'-deoxyuridines including 5-ethyl-2'-deoxyuridine (EDU) and 5-[(E)-2-(bromovinyl)]-2'-deoxyuridine (BVDU) are substrates for thymidine phosphorylase isolated from human blood platelets. Furthermore, R. Kaul, K. Keppeler, G. Kiefer, and B. Hempel (Chemosphere, Vol. 11, pages 539-540, 1982) reported the identification of the cleavage products 5-ethyluracil and 5-(2-hydroxyethyl)uracil as metabolites of EDU in rats. The biological effects of such true nucleoside analogues may be lessened by the action of these degradative enzymes. In contrast, carbocyclic analogues of nucleosides do not possess the glycosidic bond present in the true nucleosides and, therefore, are not subject to the action of these degradative enzymes. They may also be more selective in their biological actions.
The synthesis of the carbocyclic analogue (Formula I, R.dbd.CH.sub.3) of thymidine was first reported by Y. F. Shealy and C. A. O'Dell in the Journal of Heterocyclic Chemistry, Volume 13, pages 1041-1047 (1976). Additional properties of the carbocyclic analogue of thymidine and the synthesis and properties of two related carbocyclic analogues of thymine nucleosides were reported by Shealy, O'Dell, and Thorpe in the Journal of Heterocyclic Chemistry, Volume 18, pages 383-389 (1981). In this latter article in the Journal of Heterocyclic Chemistry and in an article by Shealy, O'Dell, Thorpe and Coburn, Jr., in the Journal of Heterocyclic Chemistry, Volume 20, pages 655-661 (1983), it was shown that a claim [K. C. Murdock and R. B. Angier, Journal of the American Chemical Society, Volume 84, pages 3758-3764 (1962)] that the carbocyclic analogue of thymidine had been synthesized earlier was erroneous.
Antiviral activity by the carbocyclic analogue of thymidine and by other 5-substituted-2'-deoxyribofuranosides was disclosed by Shealy et al. in an article in the Journal of Medicinal Chemistry, Volume 26, pages 156-161 (1983). U.S. Pat. No. 4,396,623 to Shealy et al discloses a method for the treatment of viral infections by treating a host animal with a pharmaceutically effective amount of a carbocyclic analogue of a nucleoside represented by the formula: ##STR2## wherein X is chlorine, bromine, iodine, a lower alkyl group or an amino group of the formula --NHR.sup.2 wherein R.sup.2 is a lower alkyl group; and R and R.sup.1 can be the same or different members selected from the group consisting of hydrogen, an alkanoyl group or an aroyl group.